Paraquat reduces natural killer cell activity via metallothionein induction

Abstract

Paraquat (PQ), one of the most widely used herbicides, has been used for several decades in agriculture. Some studies suggest that PQ has effects on the immune system. Moreover, previous studies have shown that PQ imparted some immunosuppressive effects. In the present study, cytotoxicity assays using splenic NK cells from mice treated for 28 days with PQ (at 0.2, 1, and 5 mg/kg) were performed to determine whether PQ altered the function of NK cells. Given that PQ was expected to induce an immunosuppressive effect, it was hypothesized that a gene involved in cellular metal ion homeostasis, metallothionein-1 (MT-1), could play an important role in this outcome. This belief was based on the fact that MT1 encodes a protein responsible for zinc ion homeostasis, and that a reduction in free zinc ion levels impairs NK cell function. The results showed that PQ treatments led to increased MT expression in several organs (liver, kidneys, testes) and in splenocytes, caused a reduction of both free zinc ions in sera and in free intracellular zinc, and reduced the expression of GATA-3, a zinc-finger transcription factor important for maturation and activity of T-cells and NK cells. These results provide a basis for a new molecular mechanism to describe potential immunosuppressive effects of PQ in vivo.

Regulatory Plasticity of Earthworm wMT-2 Gene Expression

“…Interestingly, in C. elegans , ELT-2 also seems to be a key regulator for the immune response, being responsible for the immune defense against pathogens in the gut [41]. The expression of GATA-3 decreased upon exposure to paraquat, which is a widely used herbicide and has an immunosuppressive character, while MT level increased and free Zn 2+ decreased in mice [42]. …”

Exposure to Dichlorodiphenyldichloroethylene (DDE) and Metallothionein Levels in Rats Fed with Normocaloric or High-Fat Diet: A Review

“…For their inducibility and their involvement in cellular responses to stress factors, nowadays MTs are considered excellent biomarkers for assessing environmental pollution not only by heavy metals [24][25][26][27], but also by many other substances of known or uncertain cellular toxicity, such as insecticides and herbicides [28][29][30][31][32][33]. For example, the exposure to the synthetic pyrethroid deltamethrin increased the MT mRNA expression levels in rainbow trout muscles [30].…”

“…The exposure to the herbicide isoproturon induces the MT expression in the aquatic oligochaeta Tubifex tubifex [31]. In vertebrates, it has been observed that MT expression increases in tissues of mice exposed to the herbicide paraquat [32], similarly to that observed in the lizard liver after treatment with the herbicide glyphosate [33]. However, a comprehensive survey on the involvement of MTs in cellular stress injury induced by pesticides is yet to appear.…”

Paraquat Preferentially Induces Apoptosis of Late Stage Effector Lymphocyte and Impairs Memory Immune Response in Mice

“…Although the immunotoxicities of PQ are complex, PQ is a confirmed toxicant to both innate and adaptive immune system [3]. For instance, PQ impaired cytotoxic capacity of nature killer (NK) cells via induction of metallothionein in mice [4]. PQ toxicities to the lung and kidney included an increased level of pro-inflammatory cytokines such as interleukin 1β (IL-1β), IL-6 and tumor necrosis factor α (TNFα) [5,6,7,8,9], indicating that innate immune cells such as macrophages and neutrophils were activated by PQ exposure.…”

“…Although a variety of studies have been performed to investigate the effects of PQ on immunity [4,14,15,16,17,18,19], to date, the influence of PQ on memory immune response remains incompletely understood. Previously, we performed numerous studies to elucidate the neurotoxicity and lung toxicity of PQ [11,24,25,26,27,28].…”